Background: Pathogenic variants of PCDH19, located on the X-chromosome (Xq22.1), cause a rare epileptic encephalopathy with speech and development delay, seizures, behavioral and psychiatric problems. The specific underlying pathogenic mechanism is known as “cellular interference” that results in affected heterozygous females, normal hemizygous males and affected mosaic males but its functioning is not yet clear. Objectives: Reporting new cases of affected males is considered useful to a deeper insight. Subject and Method: We present the case of a three-year-old boy with early-onset seizures at 3 months of age, mild cognitive impairment, partial control of seizures with levetiracetam, normal brain imaging. Results: The patient has a mosaic pathogenic variant c.698A>G (p.Asp233Gly) in PCDH19 assessed by Next Generation Sequencing analysis. We have compared his characteristics with the genotypes and phenotypes of 34 PCDH19 mosaic males earlier reported in the literature. Finally, we have summarized today’s knowledge about phenotype-genotype correlation and pharmacological response in these patients. Conclusions: Our report confirms that the clinical picture of mosaic affected males, resembling that of females, can show a wide variability in severity of disease and underlines a stringent need to improve therapeutic approaches and to collect data on long-term follow-up.

McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304–16.
Depienne C, Bouteiller D, Keren B, Cheuret E, Poirier K, Trouillard O, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009;5(2):e1000381.
Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 2000;7(1):65–73.
Vanhalst K, Kools P, Staes K, van Roy F, Redies C. Delta-Protocadherins: a gene family expressed differentially in the mouse brain. Cell Mol Life Sci. 2005;62(11):1247–59.
Gerosa L, Francolini M, Bassani S, Passafaro M. The role of protocadherin 19 (PCDH19) in neurodevelopment and in the pathophysiology of early infantile epileptic encephalopathy-9 (EIEE9). Dev Neurobiol. 2019;79(1):75–84.
Niazi R, Fanning EA, Depienne C, Sarmady M, Abou Tayoun AN. A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern. Hum Mutat. 2019;40(3):243–57.
Juberg RC, Hellman CD. A new familial form of convulsive disorder and mental retardation limited to females. J Pediatr. 1971;79(5):726–32.
Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008;40(6):776–81.
Liu A, Xu X, Yang X, Jiang Y, Yang Z, Liu X, et al. The clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. Clin Genet. 2017;91(1):54–62.
Smith L, Singhal N, El Achkar CM, Truglio G, Rosen Sheidley B, Sullivan J, et al. PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum. Epilepsia. 2018;59(3):679–89.
Kolc KL, Sadleir LG, Depienne C, Marini C, Scheffer IE, Møller RS, et al. A standardized patient-centered characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy. Transl Psychiatry. 2020;10(1):127.
Ortega-Moreno L, Giráldez BG, Soto-Insuga V, Losada-Del Pozo R, Rodrigo-Moreno M, Alarcón-Morcillo, C, et al. Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes. PLoS One. 2017;12(11):e0188978
Staněk D, Laššuthová P, Štěrbová K, Vlčková M, Neupauerová J, Krůtová M, et al. Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life. Orphanet J Rare Dis. 2018;13(1):71.
Liu A, Yang X, Yang X, Wu Q, Zhang J, Sun D, et al. Mosaicism and incomplete penetrance of PCDH19 mutations. J Med Genet. 2019;56(2):81–8.
Chen Y, Yang X, Chen J, Yang X, Yang Y, Liu, A, et al. PCDH19-related epilepsy in mosaic males: the phenotypic implication of genotype and variant allele frequency. Front Neurol. 2022;13:1041509.
Chen G, Zhou H, Lu Y, Wang Y, Li Y, Xue, J, et al. Case report: a novel mosaic nonsense mutation of PCDH19 in a Chinese male with febrile epilepsy. Front Neurol. 2022;13:992781.
Johannessen M, Kjellsen IM, Malt E. Behavioral and neuropsychological profile of a male patient with mosaic PCDH19 mutation. Epilepsy Behav Rep. 2022;19:100559.
Trivisano M, Pietrafusa N, Terracciano A, Marini C, Mei D, Darra F, et al. Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: a multicenter study. Epilepsia. 2018;59(12):2260–71.
Lotte J, Bast T, Borusiak P, Coppola A, Cross JH, Dimova P, et al. Effectiveness of antiepileptic therapy in patients with PCDH19 mutations. Seizure. 2016;35:106–10.
Bassani S, Cwetsch AW, Gerosa L, Serratto GM, Folci A, Hall IF, et al. The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological maturation of hippocampal neurons. Hum Mol Genet. 2018;27(6):1027–38.
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